Glioblastomas are extremely aggressive and lethal brain tumors. Progression from low grade glioma to glioblastoma is often associated with loss of function of the tumor suppressor phosphatase PTEN as well as overexpression of oncogenic growth factor pathways such as SF/HGF and its tyrosine kinase receptor c-met. Although the tumorigenic and malignant properties of PTEN and SF/HGF:c-met in gliomas are well documented, little is known on how they co-regulate various molecular, cellular and malignancy parameters. Since there is evidence of their direct interaction at the level of cell signaling, knowledge of their interdependencies is of importance for understanding the mechanisms that underlie glioma malignancy and for the design of cures against it. This application proposes to study how PTEN and c-met tyrosine kinase-dependent pathways co-regulate cell cycle, apoptosis, cell signaling and gene transcritiption in human gliomas. It will also test new strategies for glioma gene therapy and radio-/chemotherapy. Aim # 1 will determine how PTEN and SF/HGF:c-met co-regulate cell cycle, apoptosis and associated cell signaling and transcriptional events. Aim # 2 will determine if combining PTEN reconstitution and receptor tyrosine kinase/growth factor inhibition in vivo has therapeutic advantages. Aim #3 will determine how PTEN and receptor tyrosine kinase pathways co-regulate the expression of neoplasia-related genes in glioma cells and human tissue microarrays. These studies will provide a better understanding of the mechanistic interactions between tyrosine kinases/oncogenes and phosphatases/tumor suppressors in glioma genesis and malignancy. The studies will identify new genes that are inversely regulated by PTEN and oncogenic receptor tyrosine kinases. Analyzing the expression changes of these genes i will help understand their role in PTEN/growth factor-mediated malignancy and will lead to the identification of new candidate targets for more effective therapies. The proposed studies will also develop multi-gene targeting strategies for glioma therapy.